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Salts of 4-aniline quinazoline derivative

a quinazoline and 4-aniline technology, applied in the field of salts of 4phenylamino quinazoline derivatives, can solve the problems of excessive or deficient production of some proteins, tumor cells and cancer, excessive cell proliferation, etc., and achieve excellent tumor inhibitory activity, low toxicity, and good bioavailability

Active Publication Date: 2010-07-01
SHANGHAI ALLIST PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0042](a) It is proved by the experiments in vivo that the salts of the present invention possess excellent bioavailability;
[0038]In another aspect, the salt of the present invention can be used in the preparation of medicaments for the treatment or prevention of diseases mediated by protein tyrosine kinases. Said diseases include tumors, especially malignant tumors, such as breast cancer, non-small cell lung cancer, ovarian cancer, gastric cancer, colonic cancer, pancreatic cancer, epidermoid squamous cancer and the like.

Problems solved by technology

Said defects can be the defects of some proteins (when mutation occurs), or the lack of regulation of the amount of proteins in cell, which results in excessive or deficient production of some proteins.
However, in some case, the mutation or overexpression of any of these receptors will result in abnormal receptors and hence the uncontrolled proliferation of the cell, which may result in tumor cells and cancer in the end.
As a result, EGFR may magnify the weak signal excessively by the auto-tyrosine-kinases action, which results in excessive cell proliferation.

Method used

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  • Salts of 4-aniline quinazoline derivative
  • Salts of 4-aniline quinazoline derivative

Examples

Experimental program
Comparison scheme
Effect test

example 1

N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]quinazolin-6-yl}-acrylamide

Step A: The preparation of 4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]-6-nitro-quinazoline

[0046]1) 2.85 g (15 mmol) of 6-nitro-quinazolone and 25 ml of phosphorus oxychloride were added to a flask of 100 ml equipped with a reflux condenser and then refluxed for 3 hours at 105° C., which was then poured carefully into ice-water system of 150 ml. The squamose solid precipitated slowly. The solid was collected by filtration and dried, and was then identified as 4-chloro-6-nitro-quinazoline with a yield of 78%.

[0047]1H-NMR (400 MHz, CDCl3): δ9.22 (2H, s), 8.74 (1H, dd, J=2.57 Hz, 9.16 Hz), 8.27 (1H, d, J=9.16 Hz).

[0048]2) 4.65 g (26.6 mmol) of 2-chloro-4-nitrophenol, 3.31 ml (27.0 mmol, 1 eq) of m-fluorobenzyl bromide, 9.4 g (54 mmol, 2 eq) of potassium carbonate and 50 ml of dimethyl formamide were added to a flask of 250 ml equipped with a reflux condenser, and then heated and refluxed. The solid was remove...

example 2

The hydrochloride of N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenyl-amino]-quinazolin-6-yl}-acrylamide

[0056]1.0 g (2.23 mmol) of the compound N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenyl-amino]-quinazolin-6-yl}-acrylamide prepared according to Example 1 was dissolved in 20 mL of the mixture of ethyl acetate and triethylamine (EA / Et3N=40 / 1). The solution was stirred in an ice-water bath and thereto, 2 mL of the solution of HCl in 1,4-dioxane (4 mol / L) was added dropwise slowly. Some yellow solid precipitated, and the stir was stopped after 45 min. The solid was collected by filtration, washed with water and dried to obtain 530 mg (1.09 mmol) of Kelly solid, which was identified as the hydrochloride of N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]-quinazolin-6-yl}-acryl amide with a yield of 49%. MS: 449. mp: 249-252°.

[0057]1H-NMR (400 MHz, CDCl3+DMSO): δ8.91 (1H, s), 8.76-8.69 (2H, m), 8.01 (1H, d), 7.83 (2H, s), 7.68 (1H, dd), 7.46-7.33 (2H, m), 7.34-7.29 (2H, m), 7.23-7.18 (2H, m),...

example 3

The sulfate of N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]-quinazolin-6-yl}-acrylamide

[0059]According to the method described in Example 2, the solution of sulfuric acid in 1,4-dioxone (2 mol / L) was used instead of the solution of HCl in 1,4-dioxane (4 mol / L).

[0060]The sulfate of N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]-quinazolin-6-yl}-acrylamide was obtained.

[0061]1H-NMR (400 MHz, CDCl3+DMSO): δ8.99 (1H, s), 8.82-8.76 (2H, m), 8.10 (1H, d), 7.90 (2H, s), 7.74 (1H, dd), 7.53-7.40 (2H, m), 7.42-7.37 (2H, m), 7.31-7.26 (2H, m), 6.60 (2H, d), 6.35 (1H, t), 5.70 (2H, s).

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Abstract

The present invention relates to salt forms of N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]-quinazolin-6-yl}-acrylamide, methods for preparation thereof, pharmaceutical compositions comprising the same and their use thereof. The salt forms of the present invention, which possess excellent tumor inhibitory activity, good bioavailability and low toxicity in an animal body, are suitable for the use of preparation of anti-tumor medicaments.

Description

FIELD OF THE INVENTION[0001]The present invention relates to the salts of 4-phenylamino quinazoline derivatives. Specifically, the present invention relates to the salt forms of N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]-quinazolin-6-yl}-acrylamide, methods for preparation thereof, pharmaceutical compositions comprising the same and their use in prevention and / or treatment of tumors.BACKGROUND OF THE INVENTION[0002]Cancer is recognized as one of the diseases mediated by the signal transduction system or signal transduction mechanism in cell. The proliferation of cell is directed by many extracellular orders received by the cell. The aim of the signal transduction system is to receive these or other signals from the surface of the cell, and to introduce them into the cell. Then these signals are transmitted into nucleolus and skeleton of the cell, which affect the transcription of gene and the synthesis of protein.[0003]The most common pathogenesis of cancer is a series of def...

Claims

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Application Information

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IPC IPC(8): A61K31/517C07D239/94A61P35/00
CPCC07D239/94A61P35/00A61K31/517A61K45/06A61K2300/00
Inventor GUO, JIANHUIJIANG, YONG
Owner SHANGHAI ALLIST PHARM CO LTD
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